Severe aplastic anemia is a rare bone marrow disease which is characterized by insufficient red blood cell production. This life-threatening disease typically occurs with two peaks around 25 and 60 years of age. Bone marrow transplantation can provide cure and extended life expectancy for these individuals. For transplantation from related or unrelated donors with human leukocyte antigen (HLA) matched or closely matched, additional measures of dampening the immune response is necessary for effective engraftment. While close HLA match of donor and recipient has been the initial goal, additional differences between donor and recipient cells often cause the donor’s immune cells to attack the patient tissues, a condition termed graft-versus-host disease (GVHD). For this reason, first line treatment relies on the following immunosuppressive therapy: equine-derived anti-thymocyte globulin (ATG), cyclosporine, as well as additional agents. “Often only early results of transplant trials are reported, and one then wonders what happened to the patients long-term,” commented Dr. Joachim Deeg, a Professor Emeritus in the Clinical Research Division at Fred Hutchinson Cancer Center. Furthermore, “only observations over extended periods of time will allow [us] to determine the impact of transplantation on long-term quality of life.” Dr. Deeg and colleagues conducted a study to determine the long-term outcomes of patients with severe aplastic anemia following unrelated donor transplantation using a modified immunosuppressive regimen in preparation for transplantation. Their findings, published in EClinicalMedicine, support de-escalation of cyclophosphamide—the classically used drug to condition patients—in combination with other immunosuppressive therapies for long-term benefits for these individuals with aplastic anemia.
Bone marrow donors can be siblings or unrelated to the recipient but must have matched or closely matched HLA status with the recipient. “Results with transplants from unrelated donors for aplastic anemia (AA) are by now comparable to what can be achieved with HLA matched siblings, and our data show that this also holds true for long-term results,” shared Dr. Deeg. The study followed patients enrolled in the NCT00326417 clinical trial—a trial aimed to determine long-term outcomes of immunosuppressive therapy regimens for sustained engraftment in transplants from unrelated, HLA matched or closely matched donors for AA, as indicated above—for up to 10.5 years after receiving a transplant. The findings support long-term safety of using lower doses of cyclophosphamide (50 and 100 mg/kg instead of 150 or 200 mg/kg) with additional immunosuppressive drugs added (total body irradiation 2 Gy, ATG, and fludarabine). Specifically, the investigators found similar incidences of graft failure for either 50 or 100 mg/kg cyclophosphamide and 8-year overall survival probabilities of 85% and 76%, respectively. “The data also emphasize that complications can occur late after transplant, hence long-term follow-up is important to detect emerging complications as early as possible and thereby enhance the chance of successfully intervening,” commented Dr. Deeg. Fatal complications in the present cohort included GVHD in about 20% of recipients.
“Finally, the data illustrate the importance of "logical development" of sequential trials, by designing new trials on the basis of results from well-designed preceding studies,” stated Dr. Deeg. “I had designed a prospective multi-institutional study (in patients with AA and unrelated donors) more than 25 years ago in which we determined the optimal dose of total body irradiation. Follow-up studies then looked at the incorporation of fludarabine, in part stipulated by trials in Europe, before arriving at the present set of data.” Building upon previous clinical trials enables informed patient studies that continue to improve recommendations for standard of care.
“The present data are also important for comparison to ongoing trials in which HLA haploidentical family members (rather than unrelated individuals) are used as donors,” shared Dr. Deeg. “Those trials with haploidentical donors have yielded promising early results. Time will tell what the long-term results are going to be.”
The spotlighted research was funded by the National Institutes of Health.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Joachim Deeg contributed to this research.
Eapen M, Antin JH, Tolar J, Arai S, Horwitz ME, Kou J, Leifer E, McCarty JM, Nakamura R, Pulsipher MA, Rowley SD, Horowitz MM, Deeg HJ. 2024. Long-term survival after unrelated donor marrow transplantation for aplastic anaemia after optimized conditioning regimen: a retrospective multicentre cohort study. EClinicalMedicine. 76:102819.
Science spotlight writer Annabel Olson is a postdoctoral research fellow in the Nabet lab at Fred Hutchinson Cancer Center. Her research focuses on studying the mechanisms that drive cancer development for both genetic and virus-associated cancers. A key tool in her research is the use of targeted protein degradation to dissect dysregulated signaling pathways in cancer and to double as a relevant pre-clinical therapeutic platform.
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